Systemic lupus erythematosus (SLE) is rarely reported in association with HIV infection. We describe two unpredictable cases and provide a review of the literature. Retrospective analysis of the medical records of two HIV-infected patients diagnosed with SLE and admitted at Luigi Sacco Hospital (Milano, Italy). Search of the literature from 1981 to 2012 and review of the cases reported. Case 1: a 32-year-old HIV-infected African woman who developed a SLE flare after re-introduction of antiretroviral therapy (ART). The flare was characterized by bullous skin eruption and membranous glomerulonephritis. Case 2: a 44-year-old Caucasian woman, admitted to our hospital because of lacunar stroke: HIV infection and SLE were simultaneously diagnosed. Literature: 55 cases of SLE in the setting of HIV infection were reported. Forty-five patients met the requirements of the American College of Rheumatology for the diagnosis of SLE. The diagnosis of SLE preceded HIV infection in six patients. On the contrary, in 29 patients, HIV infection was reported before SLE. Median CD4+ count at SLE diagnosis was 361 cells/μl. A SLE manifestation following ART immune recovery was documented in 18.2% of the cases. On the contrary, the progression of HIV infection paralleled with SLE remission in 22.5% of the patients. The study shows that an autoimmune disease such as SLE can occur despite the loss of immunocompetence caused by HIV infection. Moreover, SLE and HIV infection influence each other possibly through immunologic mechanisms determining awkward manifestations.